The aim of this prospective study was to measure the contribution of maternal serum free beta-human chorionic gonadotropin (beta-hCG) in a screening program for fetal trisomy 21 based on fetal nuchal translucency in the first trimester of pregnancy. The maternal serum was collected at the time of the ultrasound scan and assayed without knowledge of the nuchal translucency measurement or karyotype. A total of 2529 pregnancies were examined (normal group, n = 2427; trisomy 21 group, n = 102). Maternal serum free beta-hCG was significantly associated with gestational age and maternal weight. In the trisomy 21 group the free beta-hCG was significantly higher than in the normals, being above the 95th centile in 29% of the cases. There was no significant association between the deviation from the mean for free beta-hCG and nuchal translucency thickness in either the normal or the trisomy 21 groups. When maternal serum free beta-hCG was added to a model based on maternal age and fetal nuchal translucency thickness, the detection rate for trisomy 21 was increased from 80% to 85%.